AP39 ameliorates uremic myocardial fibrosis in rats by upregulating PINK1/Parkin-mediated mitochondrial autophagy

Xiong SONG; Ting XIAO; Da LIU; Liangui NIE; Maojun LIU; Sen WANG; Junxiong ZHAO; Liuyang WANG; Xing LIU; Zhentao JIANG; Jun YANG

doi:10.16016/j.1000-5404.202106061

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AP39 ameliorates uremic myocardial fibrosis in rats by upregulating PINK1/Parkin-mediated mitochondrial autophagy

Basic Medicine | 更新时间：2026-01-09

- AP39 ameliorates uremic myocardial fibrosis in rats by upregulating PINK1/Parkin-mediated mitochondrial autophagy
- Journal of Third Military Medical University Vol. 43, Issue 24, Pages: 2633-2639(2021)
- 作者机构：
  
  1.421001 湖南衡阳，南华大学附属第一医院心血管内科
  2.518110 广东深圳，深圳市龙华区中心医院心血管内科
  3.421001 湖南衡阳，南华大学附属南华医院心血管内科
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81870230);the District-Level Scientific Research Project of Medical and Health Institutions in Longhua District, Shenzhen(2020035);the Youth Project of Natural Science Foundation of Hunan Province(2020JJ5505)
- DOI：10.16016/j.1000-5404.202106061
  CLC： R542.23;R692.5;R966
- Received：07 June 2021，
  
  Revised：2021-07-11，
  
  Published：30 December 2021
- 稿件说明：
移动端阅览
Xiong SONG, Ting XIAO, Da LIU, et al. AP39 ameliorates uremic myocardial fibrosis in rats by upregulating PINK1/Parkin-mediated mitochondrial autophagy[J]. Journal of Third Military Medical University, 2021, 43(24): 2633-2639.
DOI：

Xiong SONG, Ting XIAO, Da LIU, et al. AP39 ameliorates uremic myocardial fibrosis in rats by upregulating PINK1/Parkin-mediated mitochondrial autophagy[J]. Journal of Third Military Medical University, 2021, 43(24): 2633-2639. DOI： 10.16016/j.1000-5404.202106061.

摘要

目的

阐明AP39对尿毒症大鼠心肌纤维化的改善作用及机制。

方法

取40只SD雄性大鼠按随机数字表法分成4组(

=10)：假手术组(Sham组)、尿毒症心肌病模型组(UCM组)、AP39干预组(UCM+AP39)组及AP39对照组。除Sham组及AP39对照组外，另外两组大鼠采用5/6肾切除的经典手术方法建立尿毒症心肌病大鼠模型。术后UCM+AP39组及A

P39对照组大鼠予以AP39 (100 nmol/kg 1次/d)腹腔注射，Sham组及UCM组大鼠予以同等体积生理盐水腹腔注射。超声成像平台检测各组大鼠左心室缩短分数(left ventricular fractional shortening

LVFS)的变化，Masson染色观察各组大鼠心肌间质组织中胶原沉积量，免疫组化观察各组大鼠心肌组织中胶原蛋白Ⅲ(Collagen Ⅲ

Col Ⅲ)蛋白量的表达，Western blot检测PINK1、Parkin、Atg5、LC3Ⅱ/Ⅰ、Beclin1和P62(也被称为SQSTM1)等蛋白在各组大鼠心肌组织的表达水平。

结果

与Sham组相比，UCM组中大鼠的LVFS下降，心肌胶原沉积量明显增多(

0.05)，Col Ⅲ表达增多(

0.05)，心肌组织排列紊乱，并且PINK1、Parkin、Atg5、LC3Ⅱ/Ⅰ、Beclin1等蛋白的表达量明显下调(

0.05)，P62蛋白表达明显上调(

0.05)；而与UCM组相比，UCM+AP39组大鼠的LVFS升高，心肌胶原沉积量明显减少(

0.05)，Col Ⅲ表达减少(

0.05)，并且PINK1、Parkin、Atg5、LC3Ⅱ/Ⅰ和Beclin1蛋白的表达量明显上调，P62蛋白表达明显下调(

0.05)。

结论

AP39能改善尿毒症大鼠心肌纤维化，其机制可能与上调PINK1/Parkin介导的线粒体自噬有关。

Abstract

Objective

To elucidate the ameliorative effect of AP39 on myocardial fibrosis in uremic rats and investigate its possible mechanism.

Methods

Forty SD male rats were randomly and equally divided into 4 groups: Sham group

uremic cardiomyopathy group (UCM group)

AP39 intervention group (UCM+AP39 group) and AP39 control group (

=10). The rats in the UCM group and the UCM+AP39 group were treated with classical operation of 5/6 nephrectomy to establish the uremic cardiomyopathy model

and then the rats in the latter 2 groups were given intraperitoneal injection of AP39 (100 nmol/kg

once a day) for 4 weeks

while those of the Sham and model groups were intraperitoneally injected with the same amount of normal saline. Ultrasonic imaging platform was used to detect the value of left ventricular fractional shortening (LVFS) of rats in each group. Masson staining and immunohistochemical staining were performed respectively to observe collagen deposition and the expression of Collagen Ⅲ protein in the myocardial interstitial tissue of each gro

up. Western blotting was adopted to determine the expression levels of PETN-induced putative kinase-1 (PINK1)

Parkinson's disease protein (Parkin)

autophagy-related gene-5 (Atg5)

microtubule-associated protein-1 light chain-3 Ⅱ/Ⅰ(LCEⅡ/Ⅰ)

Beclin1 and P62 (also called sequestosome

SQSTM1) in the myocardial tissue of each group.

Results

As compared with those in the Sham group

the rats in the UCM group had significantly decreased LVFS

increased collagen deposition content and Collagen Ⅲ protein level (

0.05)

and disordered arrangement in myocardial tissue. The expression levels of PINK1

Parkin

Atg5

LC3Ⅱ/Ⅰand Beclin1 were significantly reduced

while the level of P62 was enhanced in the UCM group (

0.05). By contrast

the rats in the UCM+AP39 group had higher LVFS

lower collagen deposition content and Collagen Ⅲ protein level than those in the UCM group (

0.05)

the expression levels of PINK1

Parkin

Atg5

LC3 Ⅱ/Ⅰ and Beclin1 were remarkably up-regulated

and the level of P62 down-regulated (

0.05).

Conclusion

AP39 can improve uremic myocardial fibrosis in rats

which may be related to the up-regulation of PINK1/Parkin-mediated mitophagy.

关键词

Keywords

references

GARIKAPATI K, GOH D, KHANNA S, et al . Uraemic cardiomyopathy: a review of current literature[J ] . Clin Med Insights Cardiol, 2021, 15: 1179546821998347. DOI: 10.1177/1179546821998347.

谢莹, 查艳, 林鑫, 等. 曲美他嗪联合左卡尼汀治疗尿毒症心肌病的疗效观察[J]. 中国临床新医学, 2019, 12(12): 1283-1286. DOI: 10.3969/j.issn.1674-3806.2019.12.07.

XIE Y, ZHA Y, LIN X, et al . Clinical effects of trimetazidine combined with L-carnitine on treatment of uremic cardiomyopathy[J ] . Chin J New Clin Med, 2019, 12(12): 1283-1286. DOI: 10.3969/j.issn.1674-3806.2019.12.07.

张召才. 心肌纤维化的研究进展[J]. 临床心血管病杂志, 2004, 20(1): 58-60. DOI: 10.3969/j.issn.1001-1439.2004.01.028.

ZHANG Z C. Research progress of myocardial fibrosis[J]. J Clin Cardiol, 2004, 20(1): 58-60. DOI: 10.3969/j.issn.1001-1439.2004.01.028.

MEAGHER P B, LEE X A, LEE J, et al . Cardiac fibrosis: key role of integrins in cardiac homeostasis and remodeling[J ] . Cells, 2021, 10(4): 770. DOI: 10.3390/cells10040770.

CHEN L, WU Y T, GU X Y, et al . Magnolol, a natural aldehyde dehydrogenase-2 agonist, inhibits the proliferation and collagen synthesis of cardiac fibroblasts[J ] . Bioorg Med Chem Lett, 2021, 43: 128045. DOI: 10.1016/j.bmcl.2021.128045.

YUN W J, QIAN L, YUAN R Q, et al . Periplocymarin protects against myocardial fibrosis induced by β-adrenergic activation in mice[J ] . Biomedecine Pharmacother, 2021, 139: 111562. DOI: 10.1016/j.biopha.2021.111562.

LI Y L, LIU M J, SONG X, et al . Exogenous hydrogen sulfide ameliorates diabetic myocardial fibrosis by inhibiting cell aging through SIRT6/AMPK autophagy[J ] . Front Pharmacol, 2020, 11: 1150. DOI: 10.3389/fphar.2020.01150.

徐明星, 刘文秀, 梁雨亭, 等. 硫化氢在心血管疾病中的研究进展[J]. 中国现代医学杂志, 2020, 30(21): 34-38. DOI: 10.3969/j.issn.1005-8982.2020.21.007.

XU M X, LIU W X, LIANG Y T, et al . Recent research of H2S and autophagy in cardiovascular diseases[J ] . China J Mod Med, 2020, 30(21): 34-38. DOI: 10.3969/j.issn.1005-8982.2020.21.007.

SZCZESNY B, MÓDIS K, YANAGI K, et al . AP39, a nov el mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro[J ] . Nitric Oxide, 2014, 41: 120-130. DOI: 10.1016/j.niox.2014.04.008.

KARWI Q G, BORNBAUM J, BOENGLER K, et al . AP39, a mitochondria-targeting hydrogen sulfide (H 2 S) donor, protects against myocardial reperfusion injury independently of salvage kinase signalling[J ] . Br J Pharmacol, 2017, 174(4): 287-301. DOI: 10.1111/bph.13688..

LATORRE E, TORREGROSSA R, WOOD M E, et al . Mitochondria-targeted hydrogen sulfide attenuates endothelial senescence by selective induction of splicing factors HNRNPD and SRSF2[J ] . Aging (Albany NY), 2018, 10(7): 1666-1681. DOI: 10.18632/aging.101500.

ZHU C L, SU Y L, JURIASINGANI S, et al . Supplementing preservation solution with mitochondria-targeted H 2 S donor AP39 protects cardiac grafts from prolonged cold ischemia-reperfusion injury in heart transplantation[J ] . Am J Transplant, 2019, 19(11): 3139-3148. DOI: 10.1111/ajt.15539..

张妍, 刘昉. 线粒体动力学和线粒体自噬与心血管疾病的研究进展[J]. 中国心血管病研究, 2021(2): 169-174. DOI: 10.3969/j.issn.1672-5301.2021.02.015.

ZHANG Y, LIU F. Relation of mitochondrial dynamics and mitochondrial autophagy with cardiovascular disease[J]. Chin J Cardiovasc Res, 2021(2): 169-174. DOI: 10.3969/j.issn.1672-5301.2021.02.015.

YU W J, GAO B L, LI N, et al . Sirt3 deficiency exacerbates diabetic cardiac dysfunction: Role of Foxo3A-Parkin-mediated mitophagy[J ] . Biochim Biophys Acta Mol Basis Dis, 2017, 1863(8): 1973-1983. DOI: 10.1016/j.bbadis.2016.10.021.

LIU N, WU J C, ZHANG L X, et al . Hydrogen Sulphide modulating mitochondrial morphology to promote mitophagy in endothelial cells under high-glucose and high-palmitate[J ] . J Cell Mol Med, 2017, 21(12): 3190-3203. DOI: 10.1111/jcmm.13223.

梁彪. 硫化氢调控JAK2/STAT3通路抑制细胞凋亡改善尿毒症大鼠心肌纤维化[D]. 衡阳: 南华大学, 2018.

LIANG B. Hydrogen sulfide alleviates myocardial fibrosis in rats with uremia through the inhibition of apoptosis by regulating JAK2/STAT3 signaling pathway[D]. Hengyang: University of South China, 2018.

ZHAO G, ZHAO H, TU L, et al . Effects and mechanism of irbesartan on tubulointerstitial fibrosis in 5/6 nephrectomized rats[J ] . Huazhong Keji Daxue Xuebao Yixue Yingdewen Ban, 2010, 30(1): 48-54. DOI: 10.1007/s11596-010-0109-1.

WEPLER M, MERZ T, WACHTER U, et al . The mitochondria-targeted H 2 S-donor AP39 in a murine model of combined hemorrhagic shock and blunt chest trauma[J ] . Shock, 2019, 52(2): 230-239. DOI: 10.1097/shk.0000000000001210..

蒲玲. 尿毒症心肌病的诊断与治疗研究进展[J]. 疑难病杂志, 2020, 19(3): 302-306. DOI: 10.3969/j.issn.1671-6450.2020.03.020.

PU L. Research progress in diagnosis and treatment of uremic cardiomyopathy[J]. Chin J Difficult Complicat Cases, 2020, 19(3): 302-306. DOI: 10.3969/j.issn.1671-6450.2020.03.020.

易嘉莉, 聂连桂, 李亚灵, 等. 外源性硫化氢调节TGF-β1/smad7信号通路改善高同型半胱氨酸血症所致的大鼠心肌纤维化[J]. 重庆医科大学学报, 2021, 46(2): 151-155. DOI: 10.13406/j.cnki.cyxb.002569.

YI J L, NIE L G, LI Y L, et al . Exogenous hydrogen sulfide alleviates hyperhomocysteinemia-induced myocardial fibrosis in rats by regulating TGF-β1/Smad7 signaling pathway[J ] . J Chongqing Med Univ, 2021, 46(2): 151-155. DOI: 10.13406/j.cnki.cyxb.002569.

MENG G L, ZHU J B, XIAO Y J, et al . Hydrogen sulfide donor GYY4137 protects against myocardial fibrosis[J ] . Oxid Med Cell Longev, 2015, 2015: 691070. DOI: 10.1155/2015/691070.

GORTAN CAPPELLARI G, SEMOLIC A, RUOZI G, et al . Unacylated ghrelin normalizes skeletal muscle oxidative stress and prevents muscle catabolism by enhancing tissue mitophagy in experimental chronic kidney disease[J ] . FASEB J, 2017, 31(12): 5159-5171. DOI: 10.1096/fj.201700126r.

HUO S Q, SHI W, MA H Y, et al . Alleviation of inflammation and oxidative stress in pressure overload-induced cardiac remodeling and heart failure via IL-6/STAT3 inhibition by raloxifene[J ] . Oxid Med Cell Longev, 2021, 2021: 6699054. DOI: 10.1155/2021/6699054.

FAN G, CHEN M J, WEI J. Involvement of phosphatase and tensin homolog-induced putative kinase 1/Parkin-mediated autophagy in angiotensin Ⅱ-induced cardiac hypertrophy in C57BL/6 mice[J]. J Int Med Res, 2020, 48(5): 300060519896143. DOI: 10.1177/0300060519896143.

SUN Y X, YAO X, ZHANG Q J, et al . Beclin-1-dependent autophagy protects the heart during Sepsis[J ] . Circulation, 2018, 138(20): 2247-2262. DOI: 10.1161/CIRCULATIONAHA.117.032821.

BILLIA F, HAUCK L, KONECNY F, et al . PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function[J ] . Proc Natl Acad Sci USA, 2011, 108(23): 9572-9577. DOI: 10.1073/pnas.1106291108.

SUN Y, LU F H, YU X J, et al . Exogenous H 2 S promoted USP8 sulfhydration to regulate mitophagy in the hearts of db/db mice[J ] . Aging Dis, 2020, 11(2): 269-285. DOI: 10.14336/AD.2019.0524..

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